1. Field of the Invention
The present invention relates to the manufacture of 6α-fluorinated corticosteroids. In particular, the invention relates to the manufacture of 6α,9α-difluoro-11β,17α,21-trihydroxy-16α(or β)-methyl-prednisolones and their 17- and/or 21-substituted derivatives.
2. Related Art
Certain halogenated corticosteroids, particularly 6α,9α-difluoro-11β,17α21-trihydroxy-16α(or β)-methyl-prednisolones and their 17- and/or 21-substituted derivatives, represented generally by compound I (R3=Me), are known anti-inflammatory agents having pronounced activity.
Examples of compounds in this class include diflorasone (R1=OH, R3=β-methyl), flumethasone (R1=OH, R3=α-methyl), and halobetasol propionate. These agents have a 6-fluoro substituent exclusively in the alpha-(equatorial) configuration. Derivatives of these compounds, e.g., diflorasone diacetate, halobetasol propionate, flumethasone acetate etc., have also been shown to have enhanced anti-inflammatory activity.
Traditional methods for inserting fluorine in the 6-position of the steroid molecule consist of converting the corresponding 3-ketosteroids into appropriate 3-enolates and reacting these unstable intermediates with a source of electrophilic fluorine. Common sources of electrophilic fluorine that have been used are frequently toxic and gaseous, for example perfluoryl perchlorate. These known procedures generally lead to mixtures of both the 6-α- and 6-β-diastereomers which must then be separated by, for example, crystallization or column chromatography. For pregn-4-enes, the relative amount of alpha-epimer may be increased by bubbling anhydrous hydrogen chloride through a mixture of isomers in an inert organic solvent (See, for example, U.S. Pat. No. 4,036,831).
U.S. Pat. No. 4,255,331 discloses a method of preparing diflorasone derivatives which includes, as a key step, 6-fluorination of 9β,11β-epoxy-16-β-methylpregna-1,4-diene-3,20-dione 17,21-diesters. This conversion was performed in two steps by the formation of unstable 3-enolacetate and reaction of this derivative with fluoroperchlorate.
A second method (Kavolda et al. Chimia 46, 1992, pp. 338–344; Swiss. Pat. 631185; GB1563638) includes hydrogenation of the 1,2-double bond of pregna-1,4-diene-3,20-dione, preparation of the 3-ethyl enolate, 6-fluorination of the enolate by fluoroperchlorate and oxidation of the 6-fluoropreg-4-ene with DDQ to restore the pregna-1,4-diene configuration. Although this reaction proceeds with some stereoselectivity, it also utilizes the explosive and toxic gaseous fluoroperchlorate as the source of electrophilic fluoride. This reagent “has become a reagent with limited appeal. Its loss of popularity stems from difficult handling, threatening explosions, unwanted chlorinated by-products, and unavailability” (M. Hudlicky, A. E. Pavlath (ed.), “Chemistry of Organic Fluorine Compounds II”, ACS, Washington, D.C. 1995, pp. 163, 164).
There thus remains a need for safe and effective methods of preparing fluorinated steroids that are useful as anti-inflammatory agents. There is also a continuing need for methods of forming these compounds in a stereoselective manner.